In 1981, acquired immune deficiency syndrome (AIDS) was identified as a disease that severely compromises the human immune system, and that without exception leads to death. In 1983, the etiological cause of AIDS was determined to be what is now known as human immunodeficiency virus (HIV).
Another virus that causes a serious human health problem is the hepatitis B virus (HBV). HBV is second only to tobacco as a cause of human cancer. The mechanism by which HBV induces cancer is unknown. It is postulated that it may directly trigger tumor development, or indirectly trigger tumor development through chronic inflammation, cirrhosis, and cell regeneration associated with the infection.
After a 2- to 6-month incubation period, during which the host is typically unaware of the infection, HBV infection can lead to acute hepatitis and liver damage, resulting in abdominal pain, jaundice and elevated blood levels of certain enzymes. HBV can cause fulminant hepatitis, a rapidly progressive, often fatal form of the disease in which large sections of the liver are destroyed.
Patients typically recover from the acute phase of HBV infection. In some patients, however, high levels of viral antigen persist in the blood for an extended, or indefinite, period, causing a chronic infection. Chronic infections can lead to chronic persistent hepatitis. Patients infected with chronic persistent HBV are most common in developing countries. By mid-1991, there were approximately 225 million chronic carriers of HBV in Asia alone, and worldwide, almost 300 million carriers. Chronic persistent hepatitis can cause fatigue, cirrhosis of the liver, and hepatocellular carcinoma, a primary liver cancer.
In Western, industrialized countries, the high-risk group for HBV infection includes those in contact with HBV carriers or their blood samples. The epidemiology of HBV is very similar to that of HIV/AIDS, which is a reason why HBV infection is common among patients infected with HIV or suffering from AIDS. However, HBV is more contagious than HIV.
In 1985, it was reported that the synthetic nucleoside 3′-azido-3′-deoxythymidine (AZT) inhibited the replication of HIV. Since then, several other synthetic nucleosides, including but not limited to 2′,3′-dideoxyinosine (ddI), 2′,3′-dideoxycytidine (ddC), 2′,3′-dideoxy-2′,3′-didehydrothymidine (d4T), (−)-2′,3′-dideoxy-3′-thiacytidine (3TC), and (−)-carbocyclic 2′,3′-didehydro-2′,3′-dideoxyguanosine (carbovir) and its prodrug abacavir, have proven effective against HIV. After phosphorylation to the 5′-triphosphate by cellular kinases, these synthetic nucleosides are incorporated into a growing strand of viral DNA, causing chain termination, because they lack a 3′-hydroxyl group. Some nucleosides also inhibit the viral enzyme reverse transcriptase.
3TC (lamivudine) and interferon are currently the only FDA-approved drugs for the treatment of HBV infection. Viral resistance develops within 6 months of 3TC treatment in about 14% of patients.
Cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (FTC) is currently in clinical trials for the treatment of HIV and separately for HBV by Triangle Pharmaceuticals, Inc. See Schinazi et al. (1992) Selective inhibition of human immunodeficiency viruses by racemates and enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolane-5-yl]cytosine. Antimicrob. Agents Chemother. 36, 2423-2431; U.S. Pat. Nos. 5,210,085; 5,914,331; 5,814,639; WO 91/11186; and WO 92/14743.
There has also been a signficant amount of research on 1,3-dioxolane nucleosides and their use to treat viral infections. U.S. Pat. Nos. 5,210,085; 5,276,151; 5,852,027; and 5,179,104 disclose 5-fluorocytosine-1,3-dioxolane nucleoside and nucleoside analogues for the treatment of viral infections.
The success of various synthetic nucleosides in inhibiting the replication of HIV in vivo or in vitro has led a number of researchers to design and test nucleosides that substitute a heteroatom for the carbon atom at the 3′-position of the nucleoside. Norbeck, et al., disclosed that (+/−)-1-[(2-β, 4-β)-2-(hydroxymethyl)-4-dioxolanyl]thymine (referred to as (+/−)-dioxolane-T) exhibits a modest activity against HIV (EC50 of 20 μM in ATH8 cells), and is not toxic to uninfected control cells at a concentration of 200 μM. Tetrahedron Letters 30 (46), 6246, (1989).
On Apr. 11, 1988, Bernard Belleau, Dilip Dixit, and Nghe Nguyen-Ba at BioChem Pharma filed patent application U.S. Ser. No. 07/179,615 which disclosed a generic group of racemic 2-substituted-4-substituted-1,3-dioxolane nucleosides for the treatment of HIV. The '615 patent application matured into European Patent Publication No. 0 337 713; U.S. Pat. No. 5,041,449; and U.S. Pat. No. 5,270,315 assigned to BioChem Pharma, Inc.
On Dec. 5, 1990, Chung K. Chu and Raymond F. Schinazi filed U.S. Ser. No. 07/622,762, which disclosed an asymmetric process for the preparation of enantiomerically pure β-D-1,3-dioxolane nucleosides via stereospecific synthesis, and certain nucleosides prepared thereby, including (−)-(2R,4R)-9-[(2-hydroxymethyl)-1,3-dioxolan-4-yl]guanine (DXG), and its use to treat HIV. This patent application issued as U.S. Pat. No. 5,179,104. 
On May 21, 1991, Tarek Mansour, et al., at BioChem Pharma filed U.S. Ser. No. 07/703,379 directed to a method to obtain the enantiomers of 1,3-dioxolane nucleosides using a stereoselective synthesis that includes condensing a 1,3-dioxolane intermediate covalently bound to a chiral auxiliary with a silyl Lewis acid. The corresponding application filed in Europe was EP 0 515 156.
On Aug. 25, 1992, Chung K. Chu and Raymond F. Schinazi filed U.S. Ser. No. 07/935,515, disclosed certain enantiomerically pure β-D-dioxolanyl purine compounds for the treatment of humans infected with HIV of the formula: wherein R is OH, Cl, NH2, or H, or a pharmaceutically acceptable salt or derivative of the compounds optionally in a pharmaceutically acceptable carrier or diluent. The compound wherein R is chloro is referred to as (−)-(2R,4R)-2-amino-6-chloro-9-[(2-hydroxymethyl)-1,3-dioxolan-4-yl]purine. The compound wherein R is hydroxy is (−)-(2R,4R)-9-[(2-hydroxy-methyl)-1,3-dioxolan-4-yl]guanine. The compound wherein R is amino is (−)-(2R,4R)-2-amino-9-[(2-hydroxymethyl)-1,3-dioxolan-4-yl]adenine. The compound wherein R is hydrogen is (−)-(2R,4R)-2-amino-9-[(2-hydroxymethyl)-1,3-dioxolan-4yl]purine. This application issued as U.S. Pat. No. 5,925,643.
In 1992, Kim et al., published an asymmetric synthesis for selected 1,3-dioxolane pyrimidine nucleosides from 1,6-anhydro-D-mannose. The specific synthesis resulted in β-D and α-D enantiomers of 1,3-dioxolane nucleosides. Kim et al., 1,3-Dioxolanylpurine Nucleosides (2R,4R) and (2R,4S) with Selective Anti-HIV-1 Activity in Human Lymphocytes, J. Med. Chem., 1993 36, 30-37.
In 1992, Belleau et al., at BioChem Pharma, published a method to obtain enantiomerically pure 1,3-dioxolane nucleosides via L-ascorbic acid as a chiral auxiliary in the process. L-ascorbic acid was used to produce a set of diastereomers which could be separated. Belleau, et al., Oxidative Degradation of L-Ascorbic Acid Acetals to 2′,3′-Dideoxy-3′-Oxaribofuranosides Synthesis of Enantiomerically Pure 2′,3′-Dideoxy-3′-Oxaribofuranosides. Synthesis of Enantiomerically Pure 2′,3′-Dideoxy-3′-Oxacytidine Stereoisomers as Potential Antiviral Agents. Tetrahedron Lett. 1992, 33:6949.
On Feb. 21, 1992, PCT/US92/01393 (WO 92/14729) by Liotta et al. disclosed a method for the synthesis of 1,3-dioxolane nucleosides that includes condensing a 2-O-protected-5-O-acylated-1,3-dioxolane with a purine of pyrimidine base in the presence of a titanium containing Lewis acid to provide predominately the desired O-isomer in the C1′-position of a 1,3-dioxolane nucleoside. WO 92/14729 also disclosed a process for the resolution of a racemic mixture of 1,3-dioxolane nucleoside enantiomers.
In 1992, Kim et al., published an article teaching how to obtain (−)-L-β-dioxolane-C and (+)-L-β-dioxolane-T from 1,6-anhydro-L-β-glucopyranose. Kim et al., Potent anti-HIV and anti-HBV Activities of (−)-L-β-Dioxolane-C and (+)-L-β-Dioxolane-T and Their Asymmetric Syntheses, Tetrahedron Letters Vol 32(46), pp 5899-6902.
On Oct. 28, 1992, Raymond Schinazi filed U.S. Ser. No. 07/967,460 directed to the use of the compounds disclosed in U.S. Ser. No. 07/935,515 for the treatment of hepatitis B. This application has issued as U.S. Pat. Nos. 5,444,063; 5,684,010; 5,834,474; and 5,830,898.
In 1993, Jin et al., at BioChem Pharma published an article that concluded that Lewis acids play a crucial role in the preparation 1,3-dioxolane nucleosides. TiCl4 and SnCl4 promote the formation of dioxolane nucleosides with racemization in the coupling of enantiomerically pure 2′-deoxy-3′-oxaribosides with silylated N-acetylcytosine. The use of the Lewis acids trimethylsilyltriflate, trimethylsilyl iodide, and TiCl2(O-iPr)2 furnished enantiomerically pure cytosine dioxolane nucleosides in low diastereoselectivity. Unexpected Effects of Lewis Acids in the Synthesis of Optically Pure 2′-Deoxy-3′-Oxacytidine Nucleoside Analogs, Tetrahedron Asymmetry vol 4, No. 2 pp 211-214 (1993).
In 1993, Siddiqui, et al., at BioChem and Glaxo published that cis-2,6-diaminopurine dioxolane can be deaminated selectively using adenosine deaminase. Siddiqui, et al., Antiviral Optically Pure dioxolane Purine Nucleoside Analogues, Bioorganic & Medicinal Chemistry Letters, Vol. 3 (8), pp 1543-1546 (1993). (−)-(2R,4R)-2-amino-9-[(2-hydroxymethyl)-1,3-dioxolan-4-yl]adenine (DAPD) is a selective inhibitor of HIV-1 replication in vitro as a reverse transcriptase inhibitor (RTI). DAPD is thought to be deaminated in vivo by adenosine deaminase, a ubiquitous enzyme, to yield (−)-β-D-dioxolane guanine (DXG), which is subsequently converted to the corresponding 5′-tri-phosphate (DXG-TP). Biochemical analysis has demonstrated that DXG-TP is a potent inhibitor of the HIV reverse transcriptase (HIV-RT) with a Ki of 0.019 μM. 
Other nucleosides that have been successful in anti-viral treatments include of 2′,3′-dideoxy- and 2′,3′-didehydro-2,′3′-dideoxy-nucleosides (referred to as a “ddN” or “d2N” nucleoside and a “d4N” nucleoside, respectively), particularly, these nucleosides inhibit the replication of HIV in vivo or in vitro, thus, has led a number of researchers to design and test a variety of modified d2- and d4-nucleosides. One modification has been the replacement of the 5-hydrogen on cytosine nucleosides with fluorine, resulting in several 5-fluorocytosine nucleosides with antiviral activity, including but not limited to β-D- and β-L-2′,3′-dideoxy-5-fluorocytine (β-D-D2FC and β-L-D2FC) (U.S. Pat. Nos. 4,788,181 and 6,156,737).
β-D-2′,3′-Dideoxy-2′,3′-didehydro-5-fluorocytidine (d4FC) and its use to treat hepatitis B was first described in Example 2 of European Pat. Application No. 0 409 227 A2 (Ajinomoto Co., Inc.). Netherlands Pat. No. 8901258 (Stichting Rega V. Z. W.) discloses generally 5-halogeno-2′,3′-dideoxy-2′,3′-didehydrocytidine derivatives for use in treating HIV and HBV. β-D- and β-L-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine were further described in U.S. Pat. Nos. 5,703,058; 5.905,070; 6,232,300; and 5,561,120. U.S. Pat. No. 5,703,058 claims a method for the treatment of HIV and/or HBV infection that includes administering an effective amount of β-L-d4FC in combination or alternation with cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane, cis-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane, 9-[4-(hydroxymethyl)-2-cyclopenten-1-yl)-guanine (carbovir), 9-[(2-hydroxyethoxy)methyl]-guanine (acyclovir), interferon, 3′-deoxy-3′-azido-thymidine (AZT), 2′,3′-dideoxyinosine (ddI), 2′,3′-dideoxycytidine (ddC), (−)-2′-fluoro-5-methyl-β-L-ara-uridine (L-FMAU) or 2′,3′-didehydro-2′,3′-dideoxythymidine (d4T). U.S. Pat. No. 5,905,070 claims a method for the treatment of HIV and HBV infection that includes administering an effective amount of β-D-d4FC in combination or alternation with cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane, cis-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane, 9-[4-(hydroxy-methyl)-2-cyclopenten-1-yl)-guanine (carbovir), 9-[(2-hydroxyethoxy)methyl]guanine (acyclovir), interferon, 3′-deoxy-3′-azido-thymidine (AZT), 2′,3′-dideoxyinosine (ddI), 2′,3′-dideoxycytidine (ddC), (−)-2′-fluoro-5-methyl-β-L-ara-uridine (L-FMAU) or 2′,3′-didehydro-2′,3′-dideoxythymidine (d4T). U.S. Pat. No. 6,232,300 claims a method to treat HIV with β-D-d4FC.
Modification of the amino group of antiviral cytosine nucleosides has not been fully explored. Only a few N4-substituted cytosine 2′,3′-dideoxy nucleosides and N4-substituted cytosine 2′,3′-didehydro-2′,3′-dideoxy nucleosides have been reported. These include N4-benzoyl-2′,3′-didehydro-2,′3-dideoxycytidine (Kawaguchi et al., Studies on 2′,3′-dideoxy-2′,3′-didehydropyrimidine nucleosides. II. N4-benzoyl-2′,3′-dideoxy-2′,3′-didehydrocytidine as a prodrug of 2′,3′-dideoxy-2′,3′-didehydrocytidine (DDCN), Chem. Pharm. Bull. (1989), 37(9), 2547-9), N4-benzoyl-2′,3′-dideoxycytidine (Gulbis et al. (1993) Structure of a dideoxynucleoside active against the HIV (AIDS) virus. Acta Cryst. C49, 1095-1097), N4-acetyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine, and N4-isopropyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine (Shi et al. (1999)) Synthesis and biological evaluation of 2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine (d4FC) analogues: discovery of carbocyclic nucleoside triphosphates with potent inhibitory activity against HIV-1 reverse transcriptase. J. Med. Chem. 42, 859-867). Of the sugar-modified cytosine nucleosides, some N4-acyl and imine-substituted 2′,3′-dideoxy-3′-C-hydroxymethylcytidine analogues have been synthesized (Mauldin et al. (1998) Synthesis and antiviral activity of prodrugs of the nucleoside 1-[2′,3′-dideoxy-3′-C-(hydroxymethyl)-β-D-erythropentofuranosyl] cytosine. Bioorg. Med. Chem. 6, 577-585), and some N4-acetyl- and phosphonoacetyl-2′,3′-dideoxy-3′-thiacytidine nucleosides have been prepared (Charvet et al. (1993) Inhibition of human immunodeficiency virus type 1 replication by phosphonoformate- and phosphonoacetate-2′,3′-dideoxy-3′-thiacytidine conjugates. J. Med. Chem. 37, 2216-2223).
Therefore, it is an object of the present invention to provide a compound, method and composition for the treatment or prevention of HIV infection in human patients.
It is another object of the present invention to provide a compound, method and composition for the treatment or prevention of HBV infection in human patients or other host animals.
It is still another object of the present invention to provide a compound, method and composition for the treatment or prevention of HIV and HBV infection in human patients or other host animals.